Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance

Abstract

Few effective measures exist to combat the worldwide obesity epidemic, and the identification of potential therapeutic targets requires a deeper understanding of the mechanisms that control energy balance. Leptin, an adipocyte-derived hormone that signals the long-term status of bodily energy stores, acts through multiple types of leptin receptor long isoform (LepRb)-expressing neurons (called here LepRb neurons) in the brain to control feeding, energy expenditure and endocrine function. The modest contributions to energy balance that are attributable to leptin action in many LepRb populations suggest that other previously unidentified hypothalamic LepRb neurons have key roles in energy balance. Here we examine the role of LepRb in neuronal nitric oxide synthase (NOS1)-expressing LebRb (LepRb NOS1) neurons that comprise approximately 20% of the total hypothalamic LepRb neurons. Nos1 cre-mediated genetic ablation of LepRb (Lepr Nos1KO) in mice produces hyperphagic obesity, decreased energy expenditure and hyperglycemia approaching that seen in whole-body LepRb-null mice. In contrast, the endocrine functions in Lepr Nos1KO mice are only modestly affected by the genetic ablation of LepRb in these neurons. Thus, hypothalamic LepRb NOS1 neurons are a key site of action of the leptin-mediated control of systemic energy balance. © 2012 Nature America, Inc. All rights reserved.